Nitric oxide (NO) is a potent vasodilator, synthesised and released by vascular endothelial cells and plays an important role in regulating local vascular resistance and blood flow. Biologically, nitric oxide (NO) is generated from L-arginine via NO synthase enzymes and performs a variety of functions, including vasodilatation and host defence. NO is also manufactured on epithelial surfaces (such as in the mouth and stomach, and on the skin surface) in humans by sequential reduction of nitrate and nitrite. This relies on the synthesis of nitrite by the bacterial reduction of inorganic nitrate present in saliva, mucosal secretions or sweat. Nitrite is further reduced to NO in an acidic environment.
The combination of acid and nitrite is effective in killing a wide variety of pathogens by the generation of NO and oxides of nitrogen such as nitrogen dioxide (NO2). It is likely that NO generated in this way has a significant role in host defence against microbial pathogens, many of which are known to be susceptible to this agent.
A system has previously been devised that mimics this endogenous mechanism of NO generation, using inorganic nitrite and an organic acid to produce NO on the skin surface. This method relies on keeping the components separate until applied directly to the skin. Individually, these components elicit no significant effects.
WO 2000/053193 relates to the use of acidified nitrite as an agent to cause local production of nitric oxide at the skin surface for the treatment of peripheral ischaemia and associated conditions such as Raynaud's phenomenon and wounds such as post-operative wounds and burns. In some embodiments, a barrier consisting of a membrane allows diffusion of the nitrite ions while preventing direct contact of the acidifying agent with the skin.
It has also previously been discovered that a system using inorganic nitrite and an organic acid to produce NO on the skin surface can be used for the transdermal delivery of pharmaceutically active agents.
WO 02/17881 discloses a transdermal delivery system comprising a pharmaceutically active agent and acidified nitrite as an agent to cause local production of nitric oxide at the skin surface. Also disclosed is the use of a barrier consisting of a membrane to allow diffusion of the pharmaceutically active agent and nitrite ions while preventing direct contact of the acidifying agent with the skin.
WO/2014/188174 and WO/2014/188175 describe systems comprising a layer containing a nitrite and a hydrogel that contains hydrogen ions. These disclosures originate from one or more of the members of the inventive entity of the present application.